Oral administration of levo-tetrahydropalmatine attenuates reinstatement of extinguished cocaine seeking by cocaine, stress or drug-associated cues in rats

Abstract

Cocaine addiction is characterized by a persistently heightened susceptibility to drug relapse. For this reason, the identification of medications that prevent drug relapse is a critical goal of drug abuse research. Drug re-exposure, the onset of stressful life events, and exposure to cues previously associated with drug use have been identified as determinants of relapse in humans and have been found to reinstate extinguished cocaine seeking in rats. This study examined the effects of acute oral (gavage) administration of levo-tetrahydropalmatine (l-THP), a tetrahydroprotoberberine isoquinoline with a pharmacological profile that includes antagonism of D1, D2 and D3 dopamine receptors, on the reinstatement of extinguished cocaine seeking by a cocaine challenge (10mg/kg, ip), a stressor (uncontrollable electric footshock [EFS]) or response-contingent exposure to a stimulus (tone and light complex) previously associated with drug delivery in male Sprague-Dawley rats. Extinguished drug seeking was reinstated by ip cocaine, EFS, or response-contingent presentation of drug-associated cues in vehicle-pretreated rats following extinction of iv cocaine self-adminisration. Oral administration of either 3.0 or 10.0mg/kg l-THP 1h prior to reinstatement testing significantly attenuated reinstatement by each of the stimuli. Food-reinforced responding and baseline post-extinction responding were significantly attenuated at the 10.0, but not the 3.0mg/kg, l-THP dose, indicating that the effects of 3mg/kg l-THP on reinstatement were likely independent of non-specific motor impairment. These findings further suggest that l-THP may have utility for the treatment of cocaine addiction.

Figure 1

l-THP attenuates cocaine-induced reinstatement. Data represent responses on the cocaine lever during the final 6-h cocaine SA session (SA), the 2-h extinction session prior to reinstatement testing (Ext), and the 2-h reinstatement test session prior to which a 10 mg/kg (ip) injection of cocaine (Coc) was administered in rats tested for reinstatement following oral delivery of vehicle or 3 mg/kg (1A; n=7) or 10 mg/kg (1B; n=6) l-THP. Cocaine-induced reinstatement was observed following vehicle but not l-THP pretreatment (*P<0.05 vs. Ext) and l-THP pretreated rats displayed significantly less cocaine-induced reinstatement compared to Veh controls (#P<0.05 vs. Veh).

Figure 2

l-THP attenuates the reinstatement of extinguished cocaine seeking by a stressor, uncontrollable electric footshock (EFS), delivered intermittently prior to the test session. Data represent responses on the cocaine lever during the final 6-h cocaine SA session (SA), the 2-h extinction session prior to reinstatement testing (Ext), and the 2-h reinstatement test session (EFS) in rats tested for reinstatement following oral administration of vehicle or 3 mg/kg (2A; n=7) or 10 mg/kg (2B; n=6) l-THP. EFS reinstated cocaine seeking following vehicle but not l-THP pretreatment (*P<0.05 vs. Ext) and l-THP pretreated rats displayed significantly less EFS-induced cocaine seeking compared to Veh controls (#P<0.05 vs. Veh).

Figure 3

l-THP prevents the reinstatement of extinguished cocaine seeking by response contingent presentation of cues (tone-light complex) previously associated with cocaine SA. Data represent responses on the cocaine lever during the final 2-h cocaine SA session (SA), the 2-h extinction session prior to reinstatement testing (Ext), and the 2-h reinstatement test session (Cue) in rats tested for reinstatement following oral administration of vehicle or 3 mg/kg (3A; n=10) or 10 mg/kg (3B; n=7) l-THP. Cue presentation reinstated cocaine seeking following vehicle but not l-THP pretreatment (*P<0.05 vs. Ext) and l-THP pretreated rats displayed significantly less cue-induced cocaine seeking compared to Veh controls (#P<0.05 vs. Veh).

Figure 4

Effects of l-THP on baseline extinction responding. Lever pressing during the 2-h session was significantly reduced by oral administration of 10 mg/kg l-THP compared to 3 mg/kg l-THP but not vehicle (V; *P<0.05). No effects of 3 mg/kg l-THP were found.

Figure 5

Effects of l-THP on food-reinforced lever pressing. Food- (sucrose-sweetened pellet-) reinforced lever pressing under a FR4 schedule during 30 min sessions was significantly reduced by oral administration of 10 mg/kg but not 3 mg/kg l-THP (*P<0.001 vs. V).